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KMID : 0370019960100000261
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Chung-Ang Journal of Pharmacal Sciences
1996 Volume.10 No. 0 p.261 ~ p.274
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Contractions of tracheal smooth muscle from ovalbumin-sensitized guinea pigs for screening of antiasthmatic drugs
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Abstract
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Direct bronchial dilators, antihistamines, inhibitors of mast cell degranulations or glucocortioids are major therapeutics in current use against allergic asthma. However, every one of them has certain degree of drawbacks spanning from lack of full efficacy to frank side effects, restricting the long term use. There have been continuous efforts to develop new antiasthmatic agents with high efficacy and low side effects. A reliable, fast, and economic method of efficacy screening is crucial to the success of the new drug development. There have been several reports of animal models of allergic asthma, in which clinical hallmarks of asthma such as hypersensitive bronchial constriction with smooth muscle hyperreactivity and eosinophilia in alveoli and bronchial tissue were duplicated. In the current study, a fast, reliable, and economic method for the screening new antiasthmatic agents was established based on these animal models.
Hartley guinea pig was actively sensitized to ovalbumin by subcutaneous injection of ovalbumin/aluminum hydroxide mixture on day O and 14. Three weeks after the initial injection, tracheal smooth muscle strip was excised and suspended in a tissue chamber. The chamber was superfused with Krebs- Ringer bicarbonate buffer (pH 7.4) at 37 ℃ and gassed with 95% O_2, 5% CO_2 mixture. Contractions of the muscle was monitored with a isometric tension transducer.
Ovalbumin (1 ug/ml) introduced into the chamber caused a sustained contraction of the tracheal smooth muscle strips from sensitized guinea pigs, while the muscle from non-sensitized control animal did not respond. Histamine induced same degree of contractions of tracheal smooth muscle either sensitized or control animals. Three stips can be obtained from each animal, and three or more dose points were obtained on each strip either with wash between experiments or in a cumulative dosage manner. The ovalbumin- induced contraction was relaxed, in a dose-dependent manner by salbutamol, isoproterenol, theophylline or by atropine, implying direct relaxing effects of these agents, Pretreatment of the muscle strip with cromoglycate, pyrilamine, or thoephylline diminished ovalbumin-induced contractions, implying preventive effects of these agents. High potencies of pyrilamine (EC_50 = 1.00×10^-7M) and cromoglycate (EC_50 = 2.14×10^10-5M) effects suggest that ovalbumin-induced contraction is mainly due to the released histamine from mast cells, which is compatible to the known pathophysiology of allergic asthma. Using this screening model, twenty test drugs prepared from herbal resources were screened. Three drugs showed both of relaxing and preventive effects: and one showed only preventive effect. Especially, these drugs showed complete prevention when given before ovalbumine, while cromoglycate reached only 60% prevention.
In conclusion, the current model of ex vivo tracheal smooth muscle contraction from sensitized guinea pig was proved reliable, fast and economic screening methods for antiasthmatic agents under development. Some of test drugs screened so far proved effective, justifying further purification and decimalization.
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